The realm of RBM continues to evolve; the role of monitors are changing, and the way we incorporate RBM in study design and monitoring plans are reshaping the way we execute clinical trials. Moreover, non-profit organizations are now interacting with regulatory authorities to reform policies. I had the opportunity to speak to Jonathan Helfgott, former Investigator and Compliance Officer at the FDA, about the topic of changes in RBM.
Moe Alsumidaie: Can you elaborate on trends that are occurring in biopharmaceutical quality management systems (QMS)?
Jonathan Helfgott: I’m seeing trends from a vertical integration perspective, where a lot of models are trying to insource some of the key core activities of developing and managing the day-to-day operations of a functional quality system; it’s always going to be driven on the kinds of products that are needed to execute quality systems. So, if you’re bundled together on the same product types it’s much easier to stay more narrowly focused; whereas if you are managing a more diverse portfolio, you’re more likely to rely on outsourcing because the ability and practicality of developing that diverse expertise in-house is difficult.
From a senior management standpoint, the decision making points will drive the quality system. It’s almost a given that you’re relying on personnel at the front-lines that are doing the actual monitoring, who are developing the reports that are ultimately generated to reflect the overall state of compliance within a clinical trial, or a multitude of clinical trials managed in the quality system. The ability to have access to real-time information through leveraging technology combined with a strategic business perspective allows companies to implement a true quality management system.
MA: How will sourcing models change as RBM gains adoption?
JH: The “grunt work” is what’s going to be commonly outsourced, such as source data verification and monitoring visits. But, the people that are getting that dashboard view in real-time, and seeing how many patients are enrolled (a role that merges ClinOps and data management, if you will); that’s what’s being insourced now. In an outsourced model, we used to think, “okay, I’m just going to let the CROs manage the whole study and gather data;” now it’s, “we want to keep our fingers on the pulse of the study.” We don’t have the luxury anymore of letting it go all the way to the end to figure out who is first to fail. It’s a civil engineering concept: you want to fail as early as possible, you want to find out as early as possible if you don’t have a high probability of success.
MA: Can you elaborate on FDA’s approach towards implementing quality management systems?
JH: As a former FDA investigator and compliance officer, the agency has been trying to adopt its own quality management and systems approach across all levels towards clinical inspections, which applies at the highest level (Sponsors that are conducting clinical research), the applications level (submitted NDAs), and the site level (the individuals, the academic universities, and other sites that are conducting research).
FDA has also developed a risk-based site selection tool that stratifies/aggregates NDAs by clinical investigator sites, and the tool is accompanied by a draft guidance - Providing Submissions in Electronic Format - Summary Level Clinical Site Data for CDER’s Inspection Planning. This tool allows the agency to use the stratified data, and subsequently, drives decision making when selecting sites for GCP pre-approval inspections. The FDA’s ultimate purpose for investigating clinical sites is twofold: firstly, to verify appropriate Human Subject Protections & Data Quality at the site,, and secondly, the FDA tries to establish the overall state of quality for the entire study, as well as potential issues and risk indicators that could be indicative of non-compliance and potential public health issues.
MA: What types of risks/pitfalls do you expect to see as more companies start executing RBM?
JH: Making sure study teams differentiate between establishing, upfront, the critical endpoints during protocol design and monitoring plan setup, and the clinical data that’s going to be reflective of the critical safety/efficacy endpoint. If you still treat all data equally, you’re not going to be able to leverage the true value that RBM has to offer. In order to leverage RBM, companies need to use decision making based on critical data that’s as simple as a reduction in blood pressure, size of wound, and how do patients feel, etc. I find that a lot of companies realize late in the study that it’s always these particular data points that are most critical for evaluation. When study teams evaluate fifty other data points and don’t differentiate and classify upfront, based on their monitoring plan – that’s when they fall in the trap of myopia.
Another pitfall is monitors that are accessing the data in real-time without adequate data training; they don’t necessarily pay careful attention to some of the other data trails and when changes are made. As a rule of thumb, you should have 100% QC of any modification made to any data point that’s at all reflective or related to any primary safety/efficacy endpoint. The new monitoring role does not only involve looking at the information, but also training themselves on how to think in this new environment; they have to be able to adapt and keep track of any changes that study personnel and sites are making. When you implement a true RBM system, you have to take the best of the old world and merge it with a different mentality and approach. The people, processes, and technology in-place must always complement each other when implementing RBM in any clinical study.
MA: TransCelerate recently announced the development of a QMS Framework and are collaborating with regulatory authorities. Are they on the right track?
JH: Yes, I think TranCelerate, as an organization, is able to leverage the public-private partnership that’s been established with the agency, and can serve as a valuable avenue for being able to support adoption and implementation of a quality management system at every level – at the industry level, at the academic research level, and at the agency level. There are other types of public-private partnerships as well, such as Clinical Trial Transformation Initiative (CTTI) that also embarked on similar types of discussions. I think all of these efforts are extremely important in making sure that there is an equal voice, as critical decisions are made that are shaping the future of clinical development policy making.